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original article DIABETES, OBESITY AND METABOLISM The aim of the present meta-analysis is to assess the effects using the Egger’s test. Mantel–Henzel Odds Ratio (MH-OR)of metformin on the incidence of cardiovascular events and was calculated for cardiovascular events, using a random-mortality. effects model. Separate analyses were performed for trials with different comparators or exploring the effects of metformin as add-on to different therapies and for those including eitherMethods diabetic or non-diabetic patients. Separate analyses were alsoThe meta-analysis was reported following the PRISMA checklist performed for trials including patients aged <30 or >65([15], Table S1). years. A meta-regression was performed to identify moderators of the effects of metformin on cardiovascular morbidity. Baseline characteristics possibly associated with cardiovascularData Sources morbidity and mortality included metformin dose, durationAn extensive search of Medline, EMBASE and the Cochrane of trial, minimum and maximum age, HbA1c and BMI forLibrary (any date up to 31 October 2009, restricted to inclusion, as well as mean age, BMI, lipid proﬁle, HbA1c andrandomized clinical trials, published in English) was performed fasting blood glucose of patients at enrolment and proportionfor all trials containing in any ﬁeld the word ‘metformin’. No of women enrolled. All these analyses were performed usingattempt was made at identifying and retrieving unpublished Comprehensive Meta-Analysis, version 2.2.046 (NJ, USA).studies. Power calculation for each endpoint was performed on the basis of observed proportion of incident cases in control groups, using Lenth’s Piface version 1.72, and calculating theStudy Selection minimum risk reduction in the metformin group to obtain aAll trials comparing metformin with placebo, active glucose- 90% power for a p < 0.05, considering the sample sizes actuallylowering therapies, or no therapy, were included, provided that available.their duration was ≥52 weeks and that concurrent therapieswere not different in metformin and comparator arms. Thedatabase included trials in which cardiovascular events were a Resultspre-deﬁned endpoint, together with trials designed for other The process of trial retrieval and selection is summarized in(mainly metabolic) endpoints. ﬁgure 1. A total of 35 clinical trials were selected including 7171 and 11 301 participants treated with metformin andData Extraction comparator, respectively, who had 451 and 775 CV events, respectively. The median duration of trials was 112 weeksData were retrieved from the paper reporting the main (range: 52–343 weeks) with a total follow-up was 71 123results of each trial; missing information was searched for patient × years (Table 1). The number of events reported inin other publications on the same trial. Data for analysis were each trial is summarized in Table 2. Of the trials retrieved,extracted independently by two observers (C. L. and M. M.) eight did not describe major cardiovascular events. Those trialsand potential conﬂicts were resolved by a senior investigator(E. M.). Cardiovascular events were deﬁned as either fatal ornon-fatal cases of myocardial infarction, stroke and peripheral Medline/Cochrane/Embaseartery disease or other cardiovascular death. Results on all- n = 723cause and incidence of heart failure (as serious adverse event) Short (<52 weeks)were also retrieved. n = 585 Metformin in bothData Synthesis and Analysis arms n = 18The quality of trials was assessed using some of the parameters Not metforminproposed by Jadad et al. [16]. The score was not used as a n=8criterion for the selection of trials, whereas some items were Mixed therapyused only for descriptive purposes (Table S2). Heterogeneity n = 37was assessed using Q statistics; if no heterogeneity wasdetected, we applied both a random-effects and a ﬁxed-effects Not RCT n=3model. We report here the results of the random-effectsmodel, because the validity of tests of heterogeneity can Not human n=2be limited with a small number of component studies [17].Publication bias was assessed by a visual inspection of the Duplicate n = 35Begg’s funnel plot; the Egger’s test was used to providestatistical evidence of funnel plot symmetry. These tests Selected trialsare based on the unproven hypothesis that smaller studies n = 35have a greater publication bias, whereas large-scale trials areunlikely to escape public knowledge. A Begg’s Funnel plotwas drawn for the assessment of publication bias, explored Figure 1. Trial ﬂow diagram. RCT, randomized clinical trial.222 Lamanna et al. Volume 13 No. 3 March 2011

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original article DIABETES, OBESITY AND METABOLISMTable 3. Moderators of the effect of metformin treatment on cardiovascular events. Cardiovascular eventsModerator Intercept Slope pTrial duration (weeks) 0.24 [−0.06 to 0.055] −0.001 [−0.002 to − 0.0001] 0.02Age (years) −1.540 [−4.121 to 1.042] 0.02 [−0.02 to 0.07] 0.26Sex (male) 0.325 [−0.621 to 1.266] −0.007 [−0.021 to 0.019] 0.41Duration of diabetes (years) −0.143 [−0.490 to 0.203] 0.011 [−0.032 to 0.054] 0.79HbA1c at baseline (%) −1.012 [−2.670 to 0.633] 0.121 [−0.094 to 0.349] 0.26BMI at baseline (kg/m2 ) −1.721 [−4.629 to 1.177] 0.051 [−0.038 to 0.151] 0.26FPG (mg/dl) −0.421 [−1.456 to 1.0.617] 0.040 [−0.078 to 0.151] 0.50Metformin dosage (mg/day) 0.154 [−0.749 to 1.055] −0.001 [−0.0001 to 0.001] 0.63Minimum age∗ (years) −0.651 [−1.319 to 0.021] 0.021 [0.009–0.041] 0.049Maximum age∗ (years) −1.791 [−3.592 to 0.081] 0.022 [0.001–0.054] 0.050FPG, Fasting Plasma Glucose.∗ Min/Max, minimum and maximum age for inclusion in the trial.classes of drugs have been shown to be effective as glucose- single endpoints, such as myocardial infarction, stroke or heartlowering agents, at least in the short and medium term; it has failure, could have prevented the observation of some beneﬁcialbeen suggested that some of these molecules, including met- action. It should also be considered that the signiﬁcant resultformin, could confer a cardiovascular protection beyond the in studies versus placebo/no therapy is largely driven by onebeneﬁcial effect of the improvement of glucose control [6–9], trial, the UKPDS [10], the results of which are discordant frombecause of the reduction of total and LDL cholesterol, triglyc- most of other available evidence. The UKPDS was performederide body weight and blood pressure [6,7]. Furthermore, much earlier than most large-scale trials assessing the effects oftreatment with metformin is associated with enhanced ﬁb- metformin on cardiovascular events [13,21]; the greater accu-rinolysis and reduced platelet hyperaggregation [8,9]. It has racy in the treatment of extra-glycaemic cardiovascular riskalso been suggested that the reduction of hyperinsulinemia, in factors in recent years, which reduced the overall incidenceinsulin-resistant type 2 diabetic subjects, could have beneﬁcial of myocardial infarction and stroke in diabetic patients, couldeffects on cardiovascular risk [8]. have limited the possibility of further, drug-induced beneﬁcial We show here that, despite all these interesting properties, effects on cardiovascular events.metformin does not appear to have any relevant additional Differences in the characteristics of the patients enrolledeffect on cardiovascular events, apart from that determined could theoretically provide an explanation for the discrepanciesby its glucose-lowering action. Although individual studies in results of clinical trials. The meta-regression approach wasmay lack the statistical power to detect differences between used to investigate this hypothesis, showing that lower agetreatments, the meta-analytical approach overcomes this limits for inclusion are associated with a greater cardiovasculardifﬁculty, at least for the composite endpoint of all major beneﬁt of metformin. This result parallels the progressivecardiovascular events. In fact, power calculations showed that reduction of the efﬁcacy of other treatments on cardiovascularthe overall sample would have been sufﬁcient to detect a morbidity and mortality with increasing age [22]. It should alsobetween-group difference in the incidence of cardiovascular be considered that prevention of cardiovascular events usuallyevents as small as 18%. Our results conﬁrm those reported in a requires long-term treatment of risk factors; it is possible thatprevious meta-analysis which did not include some of the most the effect of metformin on this outcome could have beenrecent trials (26 trials, including RECORD [13]). Interestingly, blunted by the inclusion of some shorter-term trials.metformin was associated with a reduction of cardiovascular A trend toward a reduction in mortality was observed inrisk when compared with placebo or no therapy, whereas its patients on metformin monotherapy, in comparison witheffect disappeared when including active-comparator trials. It placebo or no treatment, but this difference did not reachcan be speculated that the cardiovascular protection conferred full statistical signiﬁcance. Considering that the number ofby metformin is largely because of the improvement of blood deaths in clinical trials is obviously smaller than that of all (fatalglucose control; this would explain the lack of additional effects and non-fatal) major cardiovascular events, the negative resultin comparison with other agents, similarly effective as glucose- could be because of an insufﬁcient sample size, particularlylowering treatments, in active-comparator trials [13]. In fact, for cardiovascular mortality. Furthermore, all-cause mortalityno beneﬁcial action of metformin on cardiovascular events includes deaths determined by causes on which metforminhas ever been reported in trials performed in non-diabetic is very unlikely to produce any effect (infections, accidents,individuals [21]. etc.). Interestingly, all-cause mortality was actually increased Metformin appeared to be associated with a reduction of car- in the two trials with events in which metformin was added todiovascular events in trials of longer duration. This suggests that a pre-existing therapy with sulphonylureas. A signiﬁcantlythe drug could have a beneﬁcial effect, which becomes evident higher mortality with metformin plus sulphonylurea inonly after several years of treatment. Furthermore, the limited comparison with sulphonylurea alone, observed in the UKPDSstatistical power to detect a protective effect of metformin on combination study had been dismissed by the authors as226 Lamanna et al. Volume 13 No. 3 March 2011

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DIABETES, OBESITY AND METABOLISM original articlea casual ﬁnding, because of the small sample size [10]; a Conﬂict of Interestsimilar, although non-signiﬁcant, result was obtained in thecomparison of sulphonylurea/metformin combination with The corresponding author conﬁrms that he had full access to all the data in the study and had ﬁnal responsibility for the decisionrosiglitazone/metformin in the RECORD trial [13]. If studies to submit for publication. C. L. has received consultancy feesin which metformin is added to a sulphonylurea are excluded from Eli Lilly, research grants from Eli Lilly, and speakingfrom the analysis, a signiﬁcant reduction of cardiovascular fees from Eli Lilly, Novo Nordisk and Sanoﬁ-Aventis. M. M.mortality, and a non-signiﬁcant trend toward a reduction has received speaking fees from Eli Lilly MSD, Guidotti andof all-cause mortality, is observed. Although those results Sanoﬁ-Aventis. N. M. has received speaking fees from Eli Lilly,are far from conclusive, the possibility of an increased Novo Nordisk and Sanoﬁ-Aventis, and research grants frommortality associated with combination therapy of metformin Eli Lilly, Novo Nordisk and Sanoﬁ-Aventis. E. M. has receivedwith sulphonylureas, which is also suggested by several consultancy fees from Eli Lilly and Novo Nordisk, speakingepidemiological studies [23,24], deserves further investigation. fees from Eli Lilly, MSD, Guidotti, Novartis, Astra Zeneca,If such a negative interaction exists, this could lead to an Novo Nordisk and Sanoﬁ-Aventis, and research grants fromunderestimation of the actual effects of metformin, per se, Eli Lilly, Novo Nordisk and Sanoﬁ-Aventis. M. M. and E. M.on all-cause and cardiovascular mortality. The mechanisms designed the study and did analysis. C. L., M. M. and E. M.underlying the potential interaction between metformin did data collection. C. L., M. M., N. M. and E. M. wrote theand sulphonylureas are presently unknown. Interestingly, in manuscript.epidemiological studies, the increase of mortality associatedwith metformin/sulpfonylurea combinations is more evidentamong patients with known coronary artery disease [25]; Supporting Informationfurthermore, the combination of metformin with glyburide is Additional Supporting Information may be found in the onlineassociated with higher mortality rates in comparison with other version of this article:drugs of the same class with lower myocardial afﬁnity [26]. On Table S1. Checklist of items to include when reporting athe basis of these data, it can be speculated that metformin systematic review or meta-analysis.potentiates the unfavourable effect of sulphonylureas on the Table S2. Characteristics of included randomized clinicalischaemic myocardium. trials. Ideally, the cardiovascular effect of a pharmacological Appendix S1. List of references.treatment should be veriﬁed through randomized trials with Please note: Wiley-Blackwell are not responsible for themajor cardiovascular events as the primary endpoint. However, content or functionality of any supporting materials suppliedadditional information can be obtained from the analysis by the authors. Any queries (other than missing material)of serious adverse events recorded in trials with other, should be directed to the corresponding author for the article.non-cardiovascular, endpoints. Recently, the Food and DrugAdministration has recommended to use such approach withphase III trials, to assess the cardiovascular safety of drugs Referencesfor diabetes prior to registration (www.fda.gov). Interestingly, 1. Nathan DM, Buse JB, Davidson MB et al. Medical management ofmetformin, unlike most older drugs, would comply with FDA hyperglycemia in type 2 diabetes: a consensus algorithm for the initiationrequirements (i.e. OR < 1 with upper conﬁdence limit <1.3 and adjustment of therapy: a consensus statement of the Americanfor major cardiovascular events). Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009; 32: 193–203. The prevention of cardiovascular disease in type 2diabetic patients requires an accurate glycaemic control [1–5]. 2. International Diabetes Federation. Global Guidelines for Type 2 Diabetes. Brussels: IDF, 2005. Available from URL: http://www.idf.org/Considering that the reduction of HbA1c is effective in the webdata/docs/IDF%20GGT2D.pdf.prevention of myocardial infarction [27–29], blood glucose 3. Meltzer S, Leiter L, Daneman D et al. Clinical practice guidelines for theshould be maintained as close to normal as possible. An management of diabetes in Canada. Can Diab Assoc 1998; 159: S1–S29.aggressive approach to hyperglycaemia in type 2 diabetesis limited by the side effects of pharmacological treatments, 4. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Medical guidelines for clinical practice for the management of diabetes mellitus.such as weight increase and hypoglycaemia [30], which could Endocrine Practice 2007; 13: 3–68.have a detrimental effect on cardiovascular mortality [27]. 5. National Institute for Health and Clinical Excellence. Type 2 diabetes:Metformin, which provides sustained glucose control with the management of type 2 diabetes. Available from URL: http://www.low hypoglycaemic risk, is a very interesting approach for nice.org.uk/CG66. Accessed 28 May 2008.cardiovascular protection. Although this drug does not appear 6. DeFronzo RA, Goodman AM, The Multicenter Metformin Study Group.to have additional beneﬁcial actions on cardiovascular events Efﬁcacy of metformin in patients with non-insulin-dependent diabetesbeyond those determined by the improvement of glucose mellitus. N Engl J Med 1995; 333: 541–549.control, the present meta-analysis excludes any adverse effect 7. Chan JC, Tomlinson B, Critchley JA, Cockram CS, Walden RJ. Metabolic andof metformin on cardiovascular morbidity and mortality. hemodynamic effects of metformin and glibenclamide in normotensiveConsidering its safety, low cost and possible effects on other, NIDDM patients. Diabetes Care 1993; 16: 1035–1038.non-cardiovascular endpoints, such as malignancies [31], the 8. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factorsuse of metformin as ﬁrst-line agent in type 2 diabetes appears for cardiovascular disease, and plasminogen activator inhibitor in NIDDMto be completely justiﬁed. subjects. A study of two ethnic groups. Diabetes Care 1993; 16: 621–629.Volume 13 No. 3 March 2011 doi:10.1111/j.1463-1326.2010.01349.x 227